title: Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial.
abstract: BACKGROUND
  Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to LDL receptors, leading to their degradation. Genetics studies have shown that loss-of-function mutations in PCSK9 result in reduced plasma LDL cholesterol and decreased risk of coronary heart disease. We aimed to investigate the safety and efficacy of ALN-PCS, a small interfering RNA that inhibits PCSK9 synthesis, in healthy volunteers with raised cholesterol who were not on lipid-lowering treatment.
  
  
  METHODS
  We did a randomised, single-blind, placebo-controlled, phase 1 dose-escalation study in healthy adult volunteers with serum LDL cholesterol of 3·00 mmol/L or higher. Participants were randomly assigned in a 3:1 ratio by computer algorithm to receive one dose of intravenous ALN-PCS (with doses ranging from 0·015 to 0·400 mg/kg) or placebo. The primary endpoint was safety and tolerability of ALN-PCS. Secondary endpoints were the pharmacokinetic characteristics of ALN-PCS and its pharmacodynamic effects on PCSK9 and LDL cholesterol. Study participants were masked to treatment assignment. Analysis was per protocol and we used ANCOVA to analyse pharmacodynamic endpoint data. This trial is registered with ClinicalTrials.gov, number NCT01437059.
  
  
  RESULTS
  Of 32 participants, 24 were randomly allocated to receive a single dose of ALN-PCS (0·015 mg/kg [n=3], 0·045 mg/kg [n=3], 0·090 mg/kg [n=3], 0·150 mg/kg [n=3], 0·250 mg/kg [n=6], or 0·400 mg/kg [n=6]) and eight to placebo. The proportions of patients affected by treatment-emergent adverse events were similar in the ALN-PCS and placebo groups (19 [79%] vs seven [88%]). ALN-PCS was rapidly distributed, with peak concentration and area under the curve (0 to last measurement) increasing in a roughly dose-proportional way across the dose range tested. In the group given 0·400 mg/kg of ALN-PCS, treatment resulted in a mean 70% reduction in circulating PCSK9 plasma protein (p<0·0001) and a mean 40% reduction in LDL cholesterol from baseline relative to placebo (p<0·0001).
  
  
  CONCLUSIONS
  Our results suggest that inhibition of PCSK9 synthesis by RNA interference (RNAi) provides a potentially safe mechanism to reduce LDL cholesterol concentration in healthy individuals with raised cholesterol. These results support the further assessment of ALN-PCS in patients with hypercholesterolaemia, including those being treated with statins. This study is the first to show an RNAi drug being used to affect a clinically validated endpoint (ie, LDL cholesterol) in human beings.
  
  
  BACKGROUND
  Alnylam Pharmaceuticals.
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, MA, USA. Electronic address: kfitzgerald@alnylam.com.
authors.forename: Kevin
authors.initials: K
authors.lastname: Fitzgerald
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Frank-Kamenetsky
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Shulga-Morskaya
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Abigail
authors.initials: A
authors.lastname: Liebow
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Bettencourt
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Sutherland
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Renta M
authors.initials: RM
authors.lastname: Hutabarat
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Clausen
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Verena
authors.initials: V
authors.lastname: Karsten
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Cehelsky
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Saraswathy V
authors.initials: SV
authors.lastname: Nochur
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Kotelianski
authors.affiliation: Internal Medicine and Molecular Genetics, University of Texas South Western, Dallas, TX, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Horton
authors.affiliation: Quintiles Drug Research Unit at Guy's Hospital, London, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Mant
authors.affiliation: Covance Clinical Research Unit, Leeds, UK.
authors.forename: Joseph
authors.initials: J
authors.lastname: Chiesa
authors.affiliation: Quintiles Drug Research Unit at Guy's Hospital, London, UK.
authors.forename: James
authors.initials: J
authors.lastname: Ritter
authors.affiliation: Covance Clinical Research Unit, Leeds, UK.
authors.forename: Malathy
authors.initials: M
authors.lastname: Munisamy
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Akshay K
authors.initials: AK
authors.lastname: Vaishnaw
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Jared A
authors.initials: JA
authors.lastname: Gollob
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Simon
mesh_terms: D000328:Adult; D008078:Cholesterol, LDL / Q000097:blood* / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D016037:Single-Blind Method
chemical_list: C585830:ALN-PCS; D008078:Cholesterol, LDL; D034741:RNA, Small Interfering; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases